The use of transdermal drug delivery systems as a means to topically administer an active agent is well known. Such systems incorporate the active agent into a carrier composition, such as a polymeric and/or pressure-sensitive adhesive composition, from which the active agent is delivered through the skin or mucosa of the user.
In general, transdermal drug delivery systems are either reservoir-type or matrix-type. Both types of systems have generally included a backing layer that forms the protective outer surface of the finished transdermal device and which is exposed to the environment during use, and a release liner or protective layer that forms the inner surface and which covers the adhesive layer for affixing the device to the skin or mucosa of a user. The release liner or protective layer is removed prior to application, exposing the adhesive layer, which is typically a pressure-sensitive adhesive. The active agent is located between the release liner and backing layer, usually solubilized or dispersed in a solvent or carrier composition.
In a reservoir-type device, the active agent, typically in fluid or gel form, is isolated from the adhesive layer used to affix the device to the user. Traditionally, a reservoir system referred to a device having a pocket or “reservoir” which served to hold the active agent and which was formed in or by the backing layer itself. A peripheral adhesive layer was then used to affix the device to the user. While such devices are still in use today, the term reservoir has become known as a device which employs one or more permeable layers, such as rate controlling membranes and drug permeable adhesives layers, laminated over the reservoir (which is typically nothing more than another layer containing the drug in a carrier composition), in order to more effectively control the delivery rate of the active agent and attachment of the device to the user.
A matrix-type device generally comprises the active agent solubilized or dispersed in an adhesive carrier composition, typically a pressure-sensitive adhesive or bioadhesive, which functions as both the drug carrier and the adhesive means of applying the system to the skin or mucosa.
A transdermal device has particular advantages over other forms of drug delivery, such as oral administration, in that the transdermal system can provide a continuous and controlled release of an active agent over a prolonged period of time, so that the resulting blood levels remain at a desired level throughout treatment. In this regard, different active agents have differing release characteristics, depending on the agent itself, as well as the matrix material it is disposed in. Further, depending on the treatment program, the desired delivery rate may be different over the treatment period. Known transdermal delivery systems in general are designed to provide constant delivery of the agent and cannot provide multiple delivery rates or varying rates over a treatment period.
As the agent is typically disposed in a single carrier composition, the delivery rate is controlled by the degree of saturation and solubility of the active agent in the carrier composition. Generally, active agents have been found to be readily soluble in acrylic polymers. However, in order to deliver a therapeutically effective amount to the system's user, and to also achieve the desired adhesive strength required for topical application in a matrix-type system, additional polymers and ingredients are often added to the carrier composition (for example, incorporating a rubber, polysiloxane or polyvinylpyrrolidone polymer).
Formulation of transdermal systems is further frequently hampered by poor solubility of certain active agents in the carrier composition, which in turn also severely limits its therapeutic application. This formulating aspect is particularly difficult in matrix-type systems because the carrier composition has to be optimized not only for the desired active agents but also for the carrier's pressure-sensitive adhesive properties. While using low concentrations in order to incorporate the active agent into the carrier may not deleteriously affect the carrier's adhesive properties, low active agent concentration can result in difficulties in achieving an acceptable delivery rate.
Generally, concentrations of the active agent up to the saturation solubility, and even supersaturated (i.e., an amount of active agent at a concentration greater than the solubility of the active agent in the carrier composition at room temperature) are sought in order to increase or maximize delivery rates. Such systems also allow for continuous administration of the active drug in therapeutically effective amounts for prolonged periods of time, such as greater than 24 hours, and even up to 7 days or more. In such systems, however, the delivery rate is again controlled by the characteristics of the carrier material, and the balance between retaining the desired adhesive qualities along with delivery of the active agent can result in less than optimum overall characteristics.
To adjust the delivery rate of such systems, attempts have been made to utilize a rate controlling membrane. Combinations of matrix reservoirs with rate-controlling membranes have also been proposed. The typical design criteria are to provide a substantially constant and continuous release rate, and to provide a release rate capable of delivering a therapeutically effective amount of the compound. More recently, dual layer transdermal delivery systems have been developed. In these systems, a drug-containing polymer adhesive layer and a second chemically distinct polymer adhesive layer not having any drug therein, are positioned adjacent one another. The second layer is applied to the skin, and is suggested as providing a rate controlling structure for controlling migration of the drug from the first layer to the skin. Alternatively in these systems, a rate controlling membrane is typically used in order to mediate the delivery of the drug from the first layer through the second layer. One problem with this system is that upon storage, the drug from the first layer can equilibrate into the second layer creating an undesirable and potentially harmful situation.
There is a need in the art for transdermal drug delivery devices in which two separate active agent-containing layers are combined prior to application to form a single, multi-layer adhesive transdermal drug delivery device. A need exists for a device of this character that allows different release rates from each layer, and the ability to deliver different concentrations and/or different agents to a user.
The drug delivery devices of the type as described above also do not allow a great amount of flexibility in effectively controlling the release rate of a drug through the patients skin from the device. The use of rate controlling membranes, or a drug-free adhesive layer in the dual layer devices provides a single release rate from the entire system. It would be desirable to provide a delivery device which allowed different release rates to be achieved for the delivery of one or more active agents through the patient's skin.